Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Hamiyet Unal is active.

Publication


Featured researches published by Hamiyet Unal.


Cell | 2015

Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

Haitao Zhang; Hamiyet Unal; Cornelius Gati; Gye Won Han; Wei Liu; Nadia A. Zatsepin; Daniel James; Dingjie Wang; Garrett Nelson; Uwe Weierstall; Michael R. Sawaya; Qingping Xu; Marc Messerschmidt; Garth J. Williams; Sébastien Boutet; Oleksandr Yefanov; Thomas A. White; Chong Wang; Andrii Ishchenko; Kalyan C. Tirupula; Russell Desnoyer; Jesse Coe; Chelsie E. Conrad; Petra Fromme; Raymond C. Stevens; Vsevolod Katritch; Sadashiva S. Karnik; Vadim Cherezov

Angiotensin II type 1 receptor (AT(1)R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT(1)R blockers (ARBs), the structural basis for AT(1)R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high-quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT(1)R in complex with its selective antagonist ZD7155 at 2.9-Å resolution. The AT(1)R-ZD7155 complex structure revealed key structural features of AT(1)R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT(1)R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT(1)R structure-function relationship and structure-based drug design.


Pharmacological Reviews | 2015

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

Sadashiva S. Karnik; Hamiyet Unal; Jacqueline R. Kemp; Kalyan C. Tirupula; Satoru Eguchi; Patrick Vanderheyden; Walter G. Thomas

The renin angiotensin system (RAS) produced hormone peptides regulate many vital body functions. Dysfunctional signaling by receptors for RAS peptides leads to pathologic states. Nearly half of humanity today would likely benefit from modern drugs targeting these receptors. The receptors for RAS peptides consist of three G-protein–coupled receptors—the angiotensin II type 1 receptor (AT1 receptor), the angiotensin II type 2 receptor (AT2 receptor), the MAS receptor—and a type II trans-membrane zinc protein—the candidate angiotensin IV receptor (AngIV binding site). The prorenin receptor is a relatively new contender for consideration, but is not included here because the role of prorenin receptor as an independent endocrine mediator is presently unclear. The full spectrum of biologic characteristics of these receptors is still evolving, but there is evidence establishing unique roles of each receptor in cardiovascular, hemodynamic, neurologic, renal, and endothelial functions, as well as in cell proliferation, survival, matrix-cell interaction, and inflammation. Therapeutic agents targeted to these receptors are either in active use in clinical intervention of major common diseases or under evaluation for repurposing in many other disorders. Broad-spectrum influence these receptors produce in complex pathophysiological context in our body highlights their role as precise interpreters of distinctive angiotensinergic peptide cues. This review article summarizes findings published in the last 15 years on the structure, pharmacology, signaling, physiology, and disease states related to angiotensin receptors. We also discuss the challenges the pharmacologist presently faces in formally accepting newer members as established angiotensin receptors and emphasize necessary future developments.


Journal of Biological Chemistry | 2015

Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor

Haitao Zhang; Hamiyet Unal; Russell Desnoyer; Gye Won Han; Nilkanth Patel; Vsevolod Katritch; Sadashiva S. Karnik; Vadim Cherezov; Raymond C. Stevens

Background: Angiotensin receptor (AT1R) blockers are critical therapeutics used to treat cardiovascular disease. Results: We solved the AT1R-olmesartan structure and identified specific interactions for olmesartan derivatives with different functions. Conclusion: Our results identified residues critical for the binding of different ligands and allosteric modulation by sodium ion. Significance: Our results provide new insights into the structural basis for ligand recognition and functional selectivity at AT1R. Angiotensin II type 1 receptor (AT1R) is the primary blood pressure regulator. AT1R blockers (ARBs) have been widely used in clinical settings as anti-hypertensive drugs and share a similar chemical scaffold, although even minor variations can lead to distinct therapeutic efficacies toward cardiovascular etiologies. The structural basis for AT1R modulation by different peptide and non-peptide ligands has remained elusive. Here, we report the crystal structure of the human AT1R in complex with an inverse agonist olmesartan (BenicarTM), a highly potent anti-hypertensive drug. Olmesartan is anchored to the receptor primarily by the residues Tyr-351.39, Trp-842.60, and Arg-167ECL2, similar to the antagonist ZD7155, corroborating a common binding mode of different ARBs. Using docking simulations and site-directed mutagenesis, we identified specific interactions between AT1R and different ARBs, including olmesartan derivatives with inverse agonist, neutral antagonist, or agonist activities. We further observed that the mutation N1113.35A in the putative sodium-binding site affects binding of the endogenous peptide agonist angiotensin II but not the β-arrestin-biased peptide TRV120027.


Journal of Biological Chemistry | 2014

Critical role for lysine 685 in gene expression mediated by transcription factor unphosphorylated STAT3.

Maupali Dasgupta; Hamiyet Unal; Belinda Willard; Jinbo Yang; Sadashiva S. Karnik; George R. Stark

Background: Lysine acetylation is an important regulatory modification of STAT3. Results: Acetylation of Lys-685 is critical for gene expression driven by unphosphorylated STAT3 (U-STAT3) but not by STAT3 phosphorylated on Tyr-705 (Y-P-STAT3). Conclusion: Distinct modifications regulate U-STAT3 and Y-P-STAT3 differentially. Significance: Lys-685 acetylation could be targeted to block U-STAT3-specific functions, such as activation of oncogene expression. STAT3 is a pleiotropic transcription factor that is activated by the phosphorylation of tyrosine 705 in response to many cytokines and growth factors. STAT3 without Tyr-705 phosphorylation (U-STAT3) is also a potent transcription factor, and its concentration in cells increases greatly in response to STAT3 activation because the STAT3 gene can be driven by phosphorylated STAT3 dimers. We have now searched for post-translational modifications of U-STAT3 that might have a critical role in its function. An analysis by mass spectroscopy indicated that U-STAT3 is acetylated on Lys-685, and the integrity of Lys-685 is required for the expression of most U-STAT3-dependent genes. In contrast, we found only a very minor role for Lys-685 in gene expression induced in response to tyrosine-phosphorylated STAT3. U-STAT3 plays an important role in angiotensin II-induced gene expression and in the consequent development of cardiac hypertrophy and dysfunction. Mutation of Lys-685 inhibits this function of STAT3, providing new information on the role of U-STAT3 in augmenting the development of heart failure.


Journal of Biological Chemistry | 2013

Long Range Effect of Mutations on Specific Conformational Changes in the Extracellular Loop 2 of Angiotensin II Type 1 Receptor

Hamiyet Unal; Rajaganapathi Jagannathan; Anushree Bhatnagar; Kalyan C. Tirupula; Russell Desnoyer; Sadashiva S. Karnik

Background: The binding of ligands to the orthosteric pocket induces ligand-specific conformational changes all through domains of G protein-coupled receptors. Results: Loss of function and gain of function mutations in the transmembrane domain spontaneously induce changes similar to a ligand-specific conformation in the extracellular domain. Conclusion: Coupling between domains determines the overall signaling state of GPCRs. Significance: Targeting domain interfaces might be the future for GPCR-specific drug development. The topology of the second extracellular loop (ECL2) and its interaction with ligands is unique in each G protein-coupled receptor. When the orthosteric ligand pocket located in the transmembrane (TM) domain is occupied, ligand-specific conformational changes occur in the ECL2. In more than 90% of G protein-coupled receptors, ECL2 is tethered to the third TM helix via a disulfide bond. Therefore, understanding the extent to which the TM domain and ECL2 conformations are coupled is useful. To investigate this, we examined conformational changes in ECL2 of the angiotensin II type 1 receptor (AT1R) by introducing mutations in distant sites that alter the activation state equilibrium of the AT1R. Differential accessibility of reporter cysteines introduced at four conformation-sensitive sites in ECL2 of these mutants was measured. Binding of the agonist angiotensin II (AngII) and inverse agonist losartan in wild-type AT1R changed the accessibility of reporter cysteines, and the pattern was consistent with ligand-specific “lid” conformations of ECL2. Without agonist stimulation, the ECL2 in the gain of function mutant N111G assumed a lid conformation similar to AngII-bound wild-type AT1R. In the presence of inverse agonists, the conformation of ECL2 in the N111G mutant was similar to the inactive state of wild-type AT1R. In contrast, AngII did not induce a lid conformation in ECL2 in the loss of function D281A mutant, which is consistent with the reduced AngII binding affinity in this mutant. However, a lid conformation was induced by [Sar1,Gln2,Ile8] AngII, a specific analog that binds to the D281A mutant with better affinity than AngII. These results provide evidence for the emerging paradigm of domain coupling facilitated by long range interactions at distant sites on the same receptor.


Advances in Experimental Medicine and Biology | 2012

Mechanism of GPCR-Directed Autoantibodies in Diseases

Hamiyet Unal; Rajaganapathi Jagannathan; Sadashiva S. Karnik

Receptor-activating autoantibodies targeting different G-protein-coupled receptors (GPCRs) have been discovered that exhibit agonist-like activity in several human pathologies. For example, autoimmune pathogenesis of Graves’ disease is attributed to autoantibody-mediated activation of the thyrotropin receptor, a GPCR. Likewise, diseases such as preeclampsia and vascular allograft rejection are caused by autoantibodies against angiotensin II type 1 receptor (AT1R). The serum of patients with Chagas disease causing congestive heart failure contains an autoantibody for the β1-adrenergic receptor. Autoantibodies against α1- and β1- and β2-adrenergic receptors found in serum from patients are linked to malignant hypertension and idiopathic dilated cardiomyopathy, respectively. Additional examples of GPCR-activating antibodies include those against the mGluR, GABA, 5HT4, calcium-sensing receptor, muscarinic M1 and M2 receptors, which have been identified in various chronic neurological diseases patients. The GPCR-directed autoantibodies may actually initiate the cellular signaling responsible for the disease since each disorder is associated with a specific GPCR-directed autoantibody. Empirical evidence suggests that the autoantibody induces GPCR activation without the endogenous ligand; however, the mechanism of antibody mediated receptor activation is not known. We show that the conformational dynamics of the extracellular domain of the AT1R generates the epitope for an autoantibody on the plasma membrane surface. This allows the antibody to bind and stabilize the activated state of AT1R, thus providing a molecular basis for the autoantibody action.


Advances in pharmacology | 2014

Constitutive Activity in the Angiotensin II Type 1 Receptor: Discovery and Applications

Hamiyet Unal; Sadashiva S. Karnik

The pathophysiological actions of the renin-angiotensin system hormone, angiotensin II (AngII), are mainly mediated by the AngII type 1 (AT1) receptor, a GPCR. The intrinsic spontaneous activity of the AT1 receptor in native tissues is difficult to detect due to its low expression levels. However, factors such as the membrane environment, interaction with autoantibodies, and mechanical stretch are known to increase G protein signaling in the absence of AngII. Naturally occurring and disease-causing activating mutations have not been identified in AT1 receptor. Constitutively active mutants (CAMs) of AT1 receptor have been engineered using molecular modeling and site-directed mutagenesis approaches among which substitution of Asn(111) in the transmembrane helix III with glycine or serine results in the highest basal activity of the receptor. Transgenic animal models expressing the CAM AT1 receptors that mimic various in vivo disease conditions have been useful research tools for discovering the pathophysiological role of AT1 receptor and evaluating the therapeutic potential of inverse agonists. This chapter summarizes the studies on the constitutive activity of AT1 receptor in recombinant as well as physiological systems. The impact of the availability of CAM AT1 receptors on our understanding of the molecular mechanisms underlying receptor activation and inverse agonism is described.


PLOS ONE | 2013

Interaction of G-Protein βγ Complex with Chromatin Modulates GPCR-Dependent Gene Regulation

Anushree Bhatnagar; Hamiyet Unal; Rajaganapathi Jagannathan; Suma Kaveti; Zhong Hui Duan; Sandro L. Yong; Amit Vasanji; Michael Kinter; Russell Desnoyer; Sadashiva S. Karnik

Heterotrimeric G-protein signal transduction initiated by G-protein-coupled receptors (GPCRs) in the plasma membrane is thought to propagate through protein-protein interactions of subunits, Gα and Gβγ in the cytosol. In this study, we show novel nuclear functions of Gβγ through demonstrating interaction of Gβ2 with integral components of chromatin and effects of Gβ2 depletion on global gene expression. Agonist activation of several GPCRs including the angiotensin II type 1 receptor specifically augmented Gβ2 levels in the nucleus and Gβ2 interacted with specific nucleosome core histones and transcriptional modulators. Depletion of Gβ2 repressed the basal and angiotensin II-dependent transcriptional activities of myocyte enhancer factor 2. Gβ2 interacted with a sequence motif that was present in several transcription factors, whose genome-wide binding accounted for the Gβ2-dependent regulation of approximately 2% genes. These findings suggest a wide-ranging mechanism by which direct interaction of Gβγ with specific chromatin bound transcription factors regulates functional gene networks in response to GPCR activation in cells.


British Journal of Pharmacology | 2017

Significance of angiotensin 1–7 coupling with MAS1 receptor and other GPCRs to the renin-angiotensin system: IUPHAR Review 22

Sadashiva S. Karnik; Khuraijam Dhanachandra Singh; Kalyan C. Tirupula; Hamiyet Unal

Angiotensins are a group of hormonal peptides and include angiotensin II and angiotensin 1–7 produced by the renin angiotensin system. The biology, pharmacology and biochemistry of the receptors for angiotensins were extensively reviewed recently. In the review, the receptor nomenclature committee was not emphatic on designating MAS1 as the angiotensin 1–7 receptor on the basis of lack of classical G protein signalling and desensitization in response to angiotensin 1–7, as well as a lack of consensus on confirmatory ligand pharmacological analyses. A review of recent publications (2013–2016) on the rapidly progressing research on angiotensin 1–7 revealed that MAS1 and two additional receptors can function as ‘angiotensin 1–7 receptors’, and this deserves further consideration. In this review we have summarized the information on angiotensin 1–7 receptors and their crosstalk with classical angiotensin II receptors in the context of the functions of the renin angiotensin system. It was concluded that the receptors for angiotensin II and angiotensin 1–7 make up a sophisticated cross‐regulated signalling network that modulates the endogenous protective and pathogenic facets of the renin angiotensin system.


Pharmacological Research | 2017

Current Topics in Angiotensin II Type 1 Receptor Research: Focus on Inverse Agonism, Receptor Dimerization and Biased Agonism

Takanobu Takezako; Hamiyet Unal; Sadashiva S. Karnik; Koichi Node

&NA; Although the octapeptide hormone angiotensin II (Ang II) regulates cardiovascular and renal homeostasis through the Ang II type 1 receptor (AT1R), overstimulation of AT1R causes various human diseases, such as hypertension and cardiac hypertrophy. Therefore, AT1R blockers (ARBs) have been widely used as therapeutic drugs for these diseases. Recent basic research and clinical studies have resulted in the discovery of interesting phenomena associated with AT1R function. For example, ligand‐independent activation of AT1R by mechanical stress and agonistic autoantibodies, as well as via receptor mutations, has been shown to decrease the inverse agonistic efficacy of ARBs, though the molecular mechanisms of such phenomena had remained elusive until recently. Furthermore, although AT1R is believed to exist as a monomer, recent studies have demonstrated that AT1R can homodimerize and heterodimerize with other G‐protein coupled receptors (GPCR), altering the receptor signaling properties. Therefore, formation of both AT1R homodimers and AT1R‐GPCR heterodimer may be involved in the pathogenesis of human disease states, such as atherosclerosis and preeclampsia. Finally, biased AT1R ligands that can preferentially activate the &bgr;‐arrestin‐mediated signaling pathway have been discovered. Such &bgr;‐arrestin‐biased AT1R ligands may be better therapeutic drugs for cardiovascular diseases. New findings on AT1R described herein could provide a conceptual framework for application of ARBs in the treatment of diseases, as well as for novel drug development. Since AT1R is an extensively studied member of the GPCR superfamily encoded in the human genome, this review is relevant for understanding the functions of other members of this superfamily. Graphical abstract Figure. No caption available.

Collaboration


Dive into the Hamiyet Unal's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Gye Won Han

University of Southern California

View shared research outputs
Top Co-Authors

Avatar

Haitao Zhang

University of Southern California

View shared research outputs
Researchain Logo
Decentralizing Knowledge