About

Dr. Wayne A. Hendrickson is the Principal Investigator of the Hendrickson Lab at Columbia University Irving Medical Center, where his research focuses on the structure and function of biological molecules. His laboratory employs advanced techniques such as x-ray crystallography, cryogenic electron microscopy (cryo-EM), and biochemical analyses to study biological macromolecules at atomic resolution. Dr. Hendrickson and his colleagues have made significant advances in diffraction methods, including stereochemically restrained refinement, phase evaluation from anomalous diffraction, the use of selenomethionyl proteins, and the development of synchrotron instrumentation. These innovations have been instrumental in establishing structural biology as a major discipline within modern biology and molecular medicine. The Hendrickson Lab applies these technologies to investigate a variety of biological systems, including membrane receptors and cellular signaling pathways, viral proteins and HIV infection mechanisms, molecular chaperones and protein folding processes, as well as structural genomics of membrane proteins. Through these studies, Dr. Hendrickson's work contributes to a deeper understanding of the molecular basis of biological function and disease.

Research topics

• Biochemistry
• Biology
• Chemistry
• Biophysics
• Cell biology
• Stereochemistry
• Crystallography
• Botany

Selected publications

• Conformational equilibria in the activation of cystine-knot hormone receptors

  Proceedings of the National Academy of Sciences · 2026-04-10

  articleOpen accessSenior authorCorresponding

  Human glycoprotein hormones such as thyroid-stimulating hormone (TSH) and follicle-stimulating hormone (FSH) belong to a broader family of cystine-knot hormones (CKHs), all of which act through leucine-rich-repeat (LRR)-containing G protein–coupled receptors (LGRs) with which they have coevolved from evolutionary predecessors in metazoan animals. There is substantial evidence for LGR dimers being required in the transmission of G-protein signals elicited by mammalian CKHs acting on their cognate LGRs. Yet, human LGRs are monomeric as extracted from cell membranes and also in cryo-EM structures, both when in apo, inactive state and when hormone bound in an LRR-elevated active state. Fortunately, the LGR from the nematode Caenorhabditis elegans ( Ce LGR) remains dimeric as detergent extracted for structure determination. In this study, we synthesize structural information from Ce LGR, Hs TSHR, and the other human LGRs together with biophysical evidence about physiological dimers to produce a theoretical description of conformational equilibria involved in CKH activation of LGRs. We develop a theory for the equilibria among conformations that govern signal transmission from hormone to G protein, we define the transitions of receptor activation in quantifiable terms, and we build and validate energetically feasible models for Ce LGR and Hs TSHR in their relevant 0:2, 1:2, and 2:2 hormone:receptor complexes. These developments provide a framework for understanding of signaling through CKH receptors and for devising structure-based hypotheses to test such conceptions.

  PublisherDOI

• Cholesterol-dependent enzyme activity of human TSPO1

  Proceedings of the National Academy of Sciences · 2025-03-27 · 5 citations

  articleOpen accessCorresponding

  The amino acid sequence of the tryptophan-rich sensory proteins (TSPO) is substantially conserved throughout all kingdoms of life. Human mitochondrial TSPO1 ( Hs TSPO1) binds to porphyrins and steroids, although its interactions with these molecules remains unknown. Hs TSPO1 is associated with numerous physiological and pathological disorders, but the underlying molecular mechanisms are unknown. Here, we disclose the finding of human mitochondrial TSPO as a cholesterol-dependent protoporphyrin IX oxygenase. The results of our biochemical characterization are consistent with structural data and evolutionary analysis. The dependence of Hs TSPO1 activity on cholesterol may be the result of the coevolution of this membrane protein with the membrane system. Our study provides a molecular foundation for comprehending the various roles played by mitochondrial TSPO in normal physiological and pathological situations.

  PublisherOA PDFDOI

• Structural and evolutionary insights into the functioning of glycoprotein hormones and their receptors

  Andrology · 2025-01-27 · 4 citations

  reviewOpen access1st authorCorresponding

  The neuroendocrine system that comprises the glycoprotein hormones (GpHs) and their receptors is essential for reproduction and metabolism. Each GpH hormone is an αβ heterodimer of cystine-knot proteins and its cognate receptor is a G-protein coupled receptor (GPCR) distinguished by a large leucine-rich-repeat (LRR) extracellular domain that binds the hormone and a class A GPCR transmembrane domain that signals through an associating heterotrimeric G protein. Hence, the receptors are called LRR-containing GPCRs-LGRs. The vertebrate GpHs and LGRs have co-evolved from homologs in the earliest metazoan animals, including sponges and comb jellies, but these are absent from unicellular organisms and plants. The two GpH subunits and accompanying LGR receptor of the nematode Caenorhabditis elegans are representative of the invertebrate evolutionary predecessors of human GpH proteins and their receptors, for example follicle-stimulating hormone (FSH) and the FSH receptor (FSHR). Atomic structures of the human GpHs and their receptors, which have been determined by X-ray crystallography and cryogenic electron microscopy (cryo-EM), inform the evolutionary process and provide a mechanistic understanding of the transmission of biochemical signals of hormone binding at the cell surface to the elicitation of second messengers such as cyclic AMP in the cytoplasm. There is compelling biochemical and cellular evidence for the importance of receptor dimers in GpH signaling in cells; yet, all of the human receptors are monomeric as defined beautifully by cryo-EM. Fortunately, the LGR of C. elegans is a stable dimer and its structure, when analyzed in the context of structural information from the human counterparts, predicts a hypothetical model for functionally relevant dimeric associations of the human GpH receptors.

  PublisherOA PDFDOI

• Structure of an LGR dimer – an evolutionary predecessor of glycoprotein hormone receptors

  Figshare · 2025-01-01

  datasetOpen accessSenior author

  wwPDB validation report, cryo-EM maps, half-maps and models

  PublisherDOI

• Structure of an LGR dimer – an evolutionary predecessor of glycoprotein hormone receptors

  Figshare · 2025-01-01

  datasetOpen accessSenior author

  wwPDB validation report, cryo-EM maps, half-maps and models

  PublisherDOI

• Structure of an LGR dimer, an evolutionary predecessor of glycoprotein hormone receptors

  Nature Communications · 2025-11-28 · 1 citations

  articleOpen accessSenior author

  Glycoprotein hormones (GpHs) produced in the human pituitary act through receptors (GpHRs) in the gonads to support reproduction and in the thyroid for metabolism. GpHs are heterodimeric cystine-knot proteins; their receptors bind cognate hormones at an extracellular domain and signal through a transmembrane domain to heterotrimeric G proteins. GpHs and GpHRs have co-evolved from invertebrate counterparts. Structures of the human receptors as isolated for cryogenic electron microscopy (cryo-EM) are all monomeric despite compelling evidence for their functioning as dimers. Here we characterize the homologous receptor from Caenorhabditis elegans. Its biochemical properties are notably similar to those of the thyroid stimulating hormone receptor (TSHR) of humans. Structurally, it is an asymmetric dimer (protomers screw-transformed by 142°/4.1 Å), composed such that only one hormone could bind. This is compatible with the 1:2 asymmetry of negatively cooperative TSH:TSHR complexes and for the transactivation evident from functional complementation of binding-deficient and signaling-deficient GpHRs. By modeling, a symmetrized dimer can bind two hormones as in the 2:2 complexes that support TSHR switches in G-protein usage. Metazoans have evolved endocrine systems that signal through dimerized receptors in response to cognate hormones. These authors characterize a nematode homolog of such human receptors, presenting the cryo-EM structure of an asymmetric dimer that embodies properties of the human receptors.

  PublisherOA PDFDOI

• The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC

  Nature Communications · 2025-12-01 · 4 citations

  articleOpen access

  HIV-1 envelope glycoproteins (Env) from primary HIV-1 isolates typically adopt a pretriggered "closed" conformation that resists to CD4-induced (CD4i) non-neutralizing antibodies (nnAbs) mediating antibody-dependent cellular cytotoxicity (ADCC). CD4-mimetic compounds (CD4mcs) "open-up" Env allowing binding of CD4i nnAbs, thereby sensitizing HIV-1-infected cells to ADCC. Two families of CD4i nnAbs, the anti-cluster A and anti-coreceptor binding site (CoRBS) Abs, are required to mediate ADCC in combination with the indane CD4mc BNM-III-170. Recently, new indoline CD4mcs with improved potency and breadth have been described. Here, we show that the lead indoline CD4mc, CJF-III-288, sensitizes HIV-1-infected cells to ADCC mediated by anti-CoRBS Abs alone, contributing to improved ADCC activity. When administrated along with the anti-CoRBS 17b, CJF-III-288 delayed viral rebound after ART interruption in HIV-1-infected humanized mice, demonstrating potential for eliciting ADCC in vivo. Structural and conformational analyses reveal that CJF-III-288, in combination with this anti-CoRBS Abs, potently stabilizes an asymmetric "open" State-3 Env conformation. This Env conformation orients the anti-CoRBS Ab to improve ADCC activity and therapeutic potential.

  PublisherOA PDFDOI

• BPS2025 - Structural and functional investigation of ryanodine receptor 1 with endogenous ligands and drugs

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• Structure of an LGR dimer – an evolutionary predecessor of glycoprotein hormone receptors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-02 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Summary The glycoprotein hormones of humans, produced in the pituitary and acting through receptors in the gonads to support reproduction and in the thyroid gland for metabolism, have co-evolved from invertebrate counterparts 1,2 . These hormones are heterodimeric cystine-knot proteins; and their receptors bind the cognate hormone at an extracellular domain and transmit the signal of this binding through a transmembrane domain that interacts with a heterotrimeric G protein. Structures determined for the human receptors as isolated for cryogenic electron microscopy (cryo-EM) are all monomeric 3–6 despite compelling evidence for their functioning as dimers 7–10 . Here we describe the cryo-EM structure of the homologous receptor from a neuroendocrine pathway that promotes growth in a nematode 11 . This structure is an asymmetric dimer that can be activated by the hormone from that worm 12 , and it shares features especially like those of the thyroid stimulating hormone receptor (TSHR). When studied in the context of the human homologs, this dimer provides a structural explanation for the transactivation evident from functional complementation of binding-deficient and signaling-deficient receptors 7 , for the negative cooperativity in hormone action that is manifest in the 1:2 asymmetry of primary TSH:TSHR complexes 8,9 , and for switches in G-protein usage that occur as 2:2 complexes form 9,10 .

  PublisherDOI

• The asymmetric opening of HIV-1 Env by a potent CD4 mimetic enables anti-coreceptor binding site antibodies to mediate ADCC

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-27 · 3 citations

  preprintOpen access

  HIV-1 envelope glycoproteins (Env) from primary HIV-1 isolates typically adopt a pretriggered "closed" conformation that resists to CD4-induced (CD4i) non-neutralizing antibodies (nnAbs) mediating antibody-dependent cellular cytotoxicity (ADCC). CD4-mimetic compounds (CD4mcs) "open-up" Env allowing binding of CD4i nnAbs, thereby sensitizing HIV-1-infected cells to ADCC. Two families of CD4i nnAbs, the anti-cluster A and anti-coreceptor binding site (CoRBS) Abs, are required to mediate ADCC in combination with the indane CD4mc BNM-III-170. Recently, new indoline CD4mcs with improved potency and breadth have been described. Here, we show that the lead indoline CD4mc, CJF-III-288, sensitizes HIV-1-infected cells to ADCC mediated by anti-CoRBS Abs alone, contributing to improved ADCC activity. Structural and conformational analyses reveal that CJF-III-288, in combination with anti-CoRBS Abs, potently stabilizes an asymmetric "open" State-3 Env conformation, This Env conformation orients the anti-CoRBS Ab to improve ADCC activity and therapeutic potential.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R37GM034102

  NIH · $3.0M · 2004

• NIH Grant U54GM095315

  NIH · $30.7M · 2016

• NIH Grant R01HL034434

  NIH · $136k · 1990

• Collaboration & Service (243-302)

  NIH · $12.6M · 2022

• Atomic Level Analysis of Biomolecular Structure

  NIH · $3.6M · 2014–2023

Frequent coauthors

• Peter D. Kwong

  National Institutes of Health

  151 shared

• Richard T. Wyatt

  Scripps Institution of Oceanography

  114 shared

• Joseph Sodroski

  Dana-Farber Cancer Institute

  109 shared

• Qun Liu

  China Agricultural University

  98 shared

• James E. Robinson

  51 shared

• Raymond W. Sweet

  41 shared

• Filippo Mancia

  36 shared

• William E. Royer

  University of Massachusetts Chan Medical School

  35 shared

Labs

• Hendrickson LabPI

Education

• B.A.

  University of Wisconsin at River Falls

• Ph.D., biophysics

  Johns Hopkins University

Awards & honors

• Ewald Prize, The International Union of Crystallography (IUC…
• Harvey Prize, Technion - Israel Institute of Technology (200…
• Canada Gairdner International Award (2003)
• Compton Award, Advanced Photon Source of Argonne National La…
• Doctor of Science honoris causa, Mount Sinai School of Medic…